Monday, November 16, 2015

The November sun was shining through the glass roof, making moving shadows that lit up the shallow end of the swimming pool. I was doing a few laps, thoroughly enjoying
my afternoon at the local rec center. I
wondered, why is it that exercise makes me feel good?

Over the last two decades, much of the research on the
neural basis of reward has focused on dopamine, a neurotransmitter that is
released by a relatively small number of neurons in the midbrain, and sent to
pretty much all the rest of the brain and other organs. When an animal sees something that it likes,
for example food, these neurons in the midbrain release dopamine. The magnitude of the release is related to
the subjective value of the rewarding stimulus.
So when you see ice cream, your brain probably releases more dopamine
than when you see broccoli.

However, when you have to work to acquire the rewarding
item, then the magnitude of dopamine release becomes smaller as the required
effort becomes larger. That is, if you
have to run a mile to get the ice cream, then the broccoli may seem like a
better choice. So it is puzzling that
exercise, which basically involves generating a lot of effort, should result in
an increase in the production of dopamine.
But there is indeed some evidence for this.

In 1994, Satoshi Hattori, Makoto Naoi, and Hitoo Nishino in
Nagoya, Japan trained 6 rats to run on a treadmill. After training, they measured dopamine levels
via micro-dialysis in a region of the basal ganglia (striatum) at 20 minute
intervals (this became the baseline measure of dopamine). They then had the animals run for 20 minutes
at a slow, medium, or fast speed, re-measured dopamine levels during the run,
and then each 20 minutes after completion of the run (for another 3 hours). They found that during the medium and fast runs,
dopamine levels increased.
Interestingly, dopamine levels remained elevated for about 1.5 hours
after completion of the run (in the figure below, the x-axis has bins of 20 minute duration). As a result,
the study demonstrated that dopamine levels increased with physical exercise, and
remained elevated beyond completion of the exercise.

But this result was in rats.
Does the same thing happen in humans?
In 2000, Gene-Jack Wang, Nora Volkow and colleagues at State University
of New York at Stony Brook asked 12 people who regularly exercised to
participate in a PET study, where they used a scanning technique to indirectly
measure dopamine levels in a region of the basal ganglia (striatum). They scanned the brain and measured dopamine
levels at baseline, and then they had the volunteers run on a treadmill for 30
minutes. Following the run, they again
scanned the brain. Surprisingly, they
found no significant changes in dopamine levels (as shown in the figure below). In these people who exercised regularly, the
run on the treadmill seemed to have had no particular effects on the dopamine
levels.

Given the results in rats, this result in humans was
puzzling, and to my knowledge still remains unresolved.

Fortunately, over the last decade there have been advances in our ability to directly record from
dopamine neurons in the primate brain. With
these recordings it is possible to see how dopamine responds to both reward and effort.

In 2015, Chiara Varazzani, Sebastian Bouret, and their
colleagues in Paris, France, trained thirsty monkeys to squeeze a handle in
order to receive juice. There were 3
juice amounts (small, medium, and large amounts of juice) and 3 amounts of effort
(small, medium, and large amounts of force), producing a total of 9
conditions.

There was a symbol associated with each of the 9 conditions. For example, when the cue was a long, narrow
rectangle, it meant that the monkey would have to squeeze the handle by a small
amount to get a small amount of juice. When
the cue was a circle, it meant that the monkey would have to squeeze by a large
amount to get the same small amount of juice.
In this way, the symbols defined both the amount of reward and the
required effort. Once the symbol was
removed, a “go” cue appeared, instructing the animal to actually produce the
force. If the animal produced the right
amount of force, it received the reward.

The authors recorded from 90 dopamine neurons in the
substantia nigra, another region in the basal ganglia, and found that when the monkey
saw the symbol indicating the reward and effort levels, the dopamine cells responded
more with increasing reward. However,
as the required effort increased, the dopamine response became smaller. Therefore, when the animal received
information regarding effort and reward contingencies of the upcoming trial, it
produced more dopamine if the trial was to include a large amount of juice, but
less dopamine if the trial was to require a large amount of force. In a sense, dopamine acted like a sum of
reward minus effort, signaling the value (or utility) of the upcoming event. At the time of cue, dopamine levels signaled
how much the animal “liked” the following trial: the brain got more dopamine if
the cue promised a lot of juice, and required only a small amount of effort.

Interestingly, during the time that the animal
actually squeezed the handle and produced the required force, dopamine cells
once again responded, but now with increased rates when the required
force was larger (in the figure below, the x-axis is time, with each interval
200ms). That is, the same cells that
earlier had reduced their discharge when told that the trial would involve a
large amount of effort, now increased their discharge during the actual production
of the large effort.

These results highlight the dual nature of dopamine. When the brain is deciding between two options
that each promise some amount of reward, and require some amount of effort,
dopamine response becomes larger with greater promised reward, and becomes
smaller with greater required effort. Maybe
this is why we tend to pick the more rewarding, less effortful option. However, when the brain is sending motor commands
to actually perform the option that we selected, dopamine responds more with
the increasing effort, and now seems impervious to the promised reward. Maybe this is why when we exercise, that is, when
we spend effort, we tend to feel as if we are rewarded: because during exercise, dopamine makes
effort seem like reward.

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About Me

I was born in Iran and immigrated to the US at the age of 14. I was educated at Gonzaga University, University of Southern California, and finally MIT. I studied under the mentorship of Prof. Michael Arbib and Prof. Emilio Bizzi. I am currently Professor of Biomedical Engineering and Neuroscience, and the Director of the BME PhD Program at Johns Hopkins School of Medicine. I am a neuroscientist who uses mathematics to understand how the brain controls our movements.